Effective Cross‐Coupling Synthesis of Novel Ethynyl‐Decorated Benzo[ b ][1,6]naphthyridines and Their Evaluation as Inhibitors of Cholinesterases and Monoamine Oxidases

An effective oxidative ethynylation of 1,2,3,4‐tetrahydrobenzo[ b ][1,6]naphthyridines (THBNs) was developed. A practical improvement was achieved by optimizing a co‐catalytic system composed of O 2 , CuI, and DMAP. The co‐catalytic system allows a decrease in the loading amount of DIAD, simplifies product isolation workup and increases the yields. The co‐catalytic system proved to be effective not only with DIAD but also with the reduced forms of DIAD‐H 2 . Supported by predictions of in‐house developed ligand‐based target fishing computational tools, a series of newly synthesized 1‐phenylethynyl‐substituted THBN derivatives were evaluated against both human cholinesterases (AChE, BChE), and monoamine oxidases (MAOs A and B) as well. Most 1‐phenylethynyl‐substituted THBNs, and the respective 1‐unsubstituted derivatives, inhibited AChE and BChE at single‐digit micromolar concentrations (IC 50 = 3–10 µM). Molecular docking simulations suggested that the ethynyl substituent may engage additional hydrophobic/π–π interactions in the AChE binding sites. Notably, 12‐chloro‐1,2,3,4‐tetrahydro‐2‐methylnaphtho[2,3‐ b ][1,6]naphthyridine ( 3a ) proved to be also a potent and selective MAO A inhibitor (IC 50 = 0.237 µM, selectivity index > 40).